| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | June 24, 2003 |
| PATENT TITLE |
Hydantoin-containing glucokinase activators |
| PATENT ABSTRACT |
Hydantoin compounds which are active as glucokinase activators to increase insulin secretion which makes them useful for treating type II diabetes. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | April 26, 2001 |
| PATENT REFERENCES CITED |
Liang Y, et al. Biochem. J. (1995) 309:167-173. Neet, K. et al, Biochemistry (1990) 29:770-777. Meglasson, M D. et al, Amer. J. Physiol. (1984) 246;E1--E13. Glaser, B. et al, New England J. Med. (1998) 338:226-230. Ferre, T. et al, Faseb J. (1996) 10:1213-1218. Grupe, A. Cell, (1995) 83:69-78. Printz, R., Ann. Rev. Nutrition, (1993) 13:463-496. Chipkin, S. et al, Joslin's Diabetes (1994) 97-115. Colowick, S., The Enzymes (1973) 9:1-48. Merrifield, R.B., Amer. Chem. Soc. (1963) 85:2149-2154. Keiser et al, Anal. Biochem. (1970) 34:595-598. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of the formula: ##STR29## wherein R.sub.1 is a five- or six-membered aromatic heterocyclic ring having one to three heteroatoms selected from nitrogen, oxygen, and sulfur, which ring is unsubstituted or substituted with halo, amino, hydroxylamino, nitro, cyano, sulfonamido, lower alkyl, perfluoro lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or --(R.sub.5).sub.n --C(O)--OR.sub.6 ; R.sub.2 is a cycloalkyl ring containing from 5 to 7 carbon atoms; R.sub.3 is hydrogen, lower alkyl, a cycloalkyl ring containing from 5 to 7 carbon atoms, unsubstituted aryl, or aryl substituted with halo or hydroxy; R.sub.4 is hydrogen or lower alkyl; R.sub.5 is --C(O)-- or lower alkyl; R.sub.6 is lower alkyl; n is 0 or 1; * and ** each designate an asymmetric centers and pharmaceutically acceptable salts thereof. 2. The compound of claim 1 wherein R.sub.1 is substituted or unsubstituted thiazolyl. 3. The compound of claim 2 wherein R.sub.1 is substituted thiazolyl. 4. The compound of claim 3 wherein R.sub.1 is thiazolyl substituted with --(R.sub.5).sub.n --C(O)--OR.sub.6. 5. The compound of claim 4 wherein R.sub.2 is cyclopentyl or cyclohexyl. 6. The compound of claim 5 wherein R.sub.3 is cyclopentyl or cyclohexyl and R.sub.4 is hydrogen. 7. The compound of claim 6 wherein n is 0. 8. A compound of claim 7 which is (S,S)-2-[[2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl)-3-cyclopenty lpropanoyl]amino]thiazole-4-carboxylic acid methyl ester. 9. A compound of claim 7 which is (S,S)-2-[[3-cyclopentyl-2-[4-(cyclopentyl)methyl-2,5-dioxoimidazolidin-1-y l]propanoyl]amino]thiazole-4-carboxylic acid methyl ester. 10. A compound of claim 7 which is (S,S)-2-[[3-cyclohexyl-2-[4-(cyclopentyl)methyl-2,5-dioxoimidazolidin-1-yl ]propanoyl]amino]thiazole-4-carboxylic acid methyl ester. 11. A compound of claim 7 wherein R.sub.2 and R.sub.3 are cyclohexyl. 12. A compound of claim 11 which is (S,S)-2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl] propanoyl]amino]thiazole-4-carboxylic acid methyl ester. 13. A compound of claim 6 wherein R.sub.2 and R.sub.3 are cyclohexyl. 14. A compound of claim 13 which is (S,S)-[2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl ]propanoyl]amino]thiazol-4-yl]oxoacetic acid ethyl ester. 15. A compound of claim 13 which is (S,S)-[2-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl ]propanoyl]amino]thiazol-4-yl]acetic acid ethyl ester. 16. A compound of claim 5 wherein R.sub.3 is substituted or unsubstituted phenyl and R.sub.4 is hydrogen. 17. A compound of claim 16 which is (S,S)-2-[[2-(4-benzyl-2,5-dioxoimidazolidin-1-yl)-3-cyclohexylpropanoyl]am ino]thiazole-4-carboxylic acid methyl ester. 18. A compound of claim 16 which is 2-[[(S)-2-[(R)-4-(4-chlorobenzyl)-2,5-dioxoimidazolidin-1-yl]-3-cyclohexyl propanoyl]amino]thiazole-4-carboxylic acid methyl ester. 19. A compound of claim 16 which is (S,S)-2-[[3-cyclohexyl-2-[2,5-dioxo-4-(4-hydroxybenzyl)imidazolidin-1-yl]p ropanoyl]amino]thiazole-4-carboxylic acid methyl ester. 20. A compound of claim 16 which is (S,S)-2-[[3-cyclohexyl-2-[2,5-dioxo-4-(3-hydroxybenzyl)imidazolidin-1-yl]p ropanoyl]amino]thiazole-4-carboxylic acid methyl ester. 21. A compound of claim 16 which is 2-[[(S)-3-cyclohexyl-2-[(R,S)-2,5-dioxo-4-(4-fluorobenzyl)imidazolidin-1-y l]propanoyl]amino]thiazole-4-carboxylic acid methyl ester. 22. A compound of claim 5 wherein at least one of R.sub.3 and R.sub.4 are lower alkyl. 23. A compound of claim 22 which is (S)-2-[[3-cyclohexyl-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)propanoyl] amino]thiazole-4-carboxylic acid methyl ester. 24. A compound of claim 22 which is 2-[[(S)-3-cyclohexyl-2-[(R)-2,5-dioxo-4-propylimidazolidin-1-yl]propanoyl] amino]thiazole-4-carboxylic acid methyl ester. 25. A compound of claim 5 wherein R.sub.3 is naphthyl and R.sub.4 is hydrogen. 26. A compound of claim 25 which is (S,S)-2-[[3-cyclohexyl-2-[2,5-dioxo-4-(naphthalen-2-yl)methylimidazolidin- 1-yl]propanoyl]amino]thiazole-4-carboxylic acid methyl ester. 27. A compound of claim 2 wherein R.sub.1 is unsubstituted thiazolyl. 28. A compound of claim 27 wherein R.sub.2 and R.sub.3 are cyclohexyl and R.sub.4 is hydrogen. 29. A compound of claim 28 which is (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]-N-( thiazole-2-yl)propanamide. 30. A compound of claim 1 wherein R.sub.1 is substituted or unsubstituted pyridine. 31. A compound of claim 30 wherein R.sub.2 is cyclohexyl. 32. A compound of claim 31 wherein R.sub.3 is cyclohexyl and R.sub.4 is hydrogen. 33. A compound of claim 32 wherein R.sub.1 is substituted pyridine. 34. A compound of claim 33 wherein the pyridine is substituted with --(R.sub.5).sub.n --C(O)--OR.sub.6. 35. A compound of claim 34 wherein n is 0 and R.sub.6 is lower alkyl. 36. A compound of claim 35 which is (S,S)-6-[[3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl] propanoyl]amino]nicotinic acid methyl ester. 37. A compound of claim 33 which is (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]-N-( 5-methylpyridin-2-yl)propanamide. 38. A compound of claim 33 which is (S,S)-N-(5-chloropyridin-2-yl)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-di oxoimidazolidin-1-yl]propanamide. 39. A compound of claim 32 wherein R.sub.1 is unsubstituted pyridine. 40. A compound of claim 39 which is (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]-N-( pyridin-2-yl)propanamide. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic .beta.-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in Joslin's Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (.apprxeq.10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in .beta.-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in .beta.-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production. The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in .beta.-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes. SUMMARY OF THE INVENTION This invention provides a compound, comprising a substituted hydantoin of the formula: ##STR1## wherein R.sub.1 is a five- or six-membered aromatic heterocyclic ring having one to three heteroatoms selected from nitrogen, oxygen, and sulfur, which ring is unsubstituted or substituted with halo, amino, hydroxylamino, nitro, cyano, sulfonamido, lower alkyl, perfluoro lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or --(R.sub.5).sub.n --C(O)--OR.sub.6 ; R.sub.2 is a cycloalkyl ring containing from 5 to 7 carbon atoms; R.sub.3 is hydrogen, lower alkyl, a cycloalkyl ring containing from 5 to 7 carbon atoms, unsubstituted aryl, aryl substituted with halo or hydroxy, or an unsubstituted five- or six-membered aromatic heterocyclic ring having one or two heteroatoms selected from nitrogen, oxygen, and sulfur; R.sub.4 is hydrogen, lower alkyl, or R.sub.3 and R.sub.4 together with the carbon atom to which they are attached form a cycloalkyl ring containing 5 to 7 carbon atoms; R.sub.5 is --C(O)-- or lower alkyl; R.sub.6 is lower alkyl; n is 0 or 1; * and ** each designate an asymmetric centers, and pharmaceutically acceptable salts thereof. The compounds of Formula I have been found to activate glucokinase. Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes. Therefore compounds of this invention are useful to increase insulin secretion in view of their activity as glucokinase activators. |
| PATENT PHOTOCOPY | Available on request |
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